期刊
CELL
卷 142, 期 4, 页码 601-612出版社
CELL PRESS
DOI: 10.1016/j.cell.2010.07.020
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资金
- GUIDE
- Wellcome Trust
- MRC Program
- NIA [P01 AG031097]
- ZonMw Research Institute of the Elderly
- Prinses Beatrix Fonds
- de Vereniging van Huntington
- Nederlandse Hersenstichting
- UMCG Rosalind Franklin Fellowship
- MRC [G0600194] Funding Source: UKRI
- Medical Research Council [G0600194] Funding Source: researchfish
Fibrillar protein aggregates are the major pathological hallmark of several incurable, age-related, neurodegenerative disorders. These aggregates typically contain aggregation-prone pathogenic proteins, such as amyloid-beta in Alzheimer's disease and alpha-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates are formed during cellular aging. Here we identify an evolutionarily highly conserved modifier of aggregation, MOAG-4, as a positive regulator of aggregate formation in C. elegans models for polyglutamine diseases. Inactivation of MOAG-4 suppresses the formation of compact polyglutamine aggregation intermediates that are required for aggregate formation. The role of MOAG-4 in driving aggregation extends to amyloid-beta and alpha-synuclein and is evolutionarily conserved in its human orthologs SERF1A and SERF2. MOAG-4/SERF appears to act independently from HSF-1-induced molecular chaperones, proteasomal degradation, and autophagy. Our results suggest that MOAG-4/SERF regulates age-related proteotoxicity through a previously unexplored pathway, which will open up new avenues for research on age-related, neurodegenerative diseases.
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